1. Field of the Invention
This invention relates to a novel method of inhibiting detrusor muscle spasticity while simultaneously increasing the force of normal detrusor muscle contraction. Such an invention has many novel applications including but not limited to the treatment of patients suffering from unstable bladder conditions.
2. Description of the Prior Art
The human bladder is composed of four coats; serous, muscular, submucous and mucous. The muscular coat consists of three layers of unstriped muscular fiber: an external layer, composed of fibers having for the most part a longitudinal arrangement; a middle layer in which the fibers are arranged, more or less, in a circular manner; and an internal layer, in which the fibers have a general longitudinal arrangement. In the external longitudinal layer at the sides of the bladder, the muscle fibers are arranged obliquely and intersect one another. This layer is called the detrusor muscle.
Thiphenamil hydrochloride is a class of compounds comprising a di-N-substituted aminoethyl ester of diphenylthioacetic acid having the formula: ##STR2## in which R represents a disubstituted amino radical of either the diethylamino group, the morpholino group or the piperidino group.
The prior uses for thiphenamil hydrochloride center around its use as an anti-spasmodic agent in the upper and lower gasto-intestinal tract for pylorospasm, spasm associated with the gallbladder and common bile duct, as well as diarrhea and the irritable bowel syndrome. Prior art uses also include treatment of ureterospasm and bladder irritation.
There have been further reports that thiphenamil hydrochloride has been successfully used for the treatment of bronchospasm.
Thiphenamil hydrochloride is a well-known compound and is described in detail in U.S. Pat. No. 2,390,555 to Richardson, incorporated herein by reference. Additional methods of making thiphenamil hydrochloride are described in U.S. Pat. No. 2,510,773 to Clinton.
The term "detrusor instability" generally refers to the condition wherein the bladder spontaneously contracts and empties before the patient is ready.
Generally, the following compounds have been used for the pharmacological treatment of detrusor instability: "URISPAS" (flavoxate hydrochloride) which is a smooth muscle relaxant; "DITROPAN" (oxybutynin chloride) an anti-cholinergic used for the relief of neurogenic bladder symptoms; and "BANTHINE" (methantheline bromide) an anti-cholinergic and anti-spasmodic drug. For the most part, the above listed and other derivatives of atropine are unpredictable in their effect on bladder instability. In addition to their rather poor successful treatment record, anti-cholinergic compounds produce undesirable side effects such as dryness of the mouth, dilation of the pupils and slowed heartbeat.
In the uses of thiphenamil hydrochloride as a smooth muscle relaxant it has generally been assumed that the drug relaxes and inhibits the ability of smooth muscles to contract. This phenomenon has been shown in a number of studies:
1. STUDIES ON THE PHARMACOLOGY OF BETA-DIETHYLAMINOETHYLDIPHENYLTHIOACETATE, A SYNTHETIC ANTISPASMODIC, Ramsey & Richardson, J. Pharm. & Exp. Th., February 1947, pp. 131-142. PA0 2. CLINICAL EVALUATION OF TROCINATE, AN ANTISPASMODIC, MacDonald, J. Missouri Medical Association, September 1951, pp. 685-6. PA0 3. USE OF ANTISPASMODICS IN TREATMENT OF SPASTIC URETERITIS, Thackston et. al., J. Urology, March 1955, pp. 487-493. PA0 4. EFFECT OF A LOCAL SMOOTH MUSCLE ANTAGONIST ON WOUND CONTRACTION, Morton et. al., Surg. Forum, Vol. 23, 1972. PA0 5. MUSCLE DRUG SLOWS WOUND CONTRACTION, Medical World News, March 1974, p. 74A. PA0 6. CONTRACTION OF EXPERIMENTAL WOUNDS I. INHIBITING WOUND CONTRACTION BY USING A TOPICAL SMOOTH MUSCLE ANTAGONIST, Madden et. al., Surgery, July 1974, pp. 8-15.
As a result of these and other studies, persons skilled in the art generally expect the force of the smooth muscle contractions to be greatly diminished after administering thiphenamil hydrochloride.
There has been a need in the pharmaceutical art for a drug which inhibits involuntary detrusor contractions while at the same time increasing the strength of voluntary detrusor contractions.
Thus, it is an important object of the present invention to provide a method for inhibiting unplanned or premature muscle contraction of the detrusor muscle while at the same time increasing the force of voluntary contraction of the detrusor muscle.
It is yet another important object of the present invention to provide such a method which is safe for use on human patients, particularly sensitive patients such as glaucoma patients, without subjecting the patient to the undesirable side effects of anti-cholinergic drugs, for example dryness of the mouth, dilation of the pupils and slowed hearbeat.
It is another important object of the present invention to provide such a method of inhibiting unplanned or premature muscle contraction while at the same time increasing the force of the detrusor muscle contraction without leaving or accumulating any foreign substances in the human body tissues.